In U.S. Pat. Nos. 4,479,932 and 4,540,564 detailed reference is made to the well established fact that the delivery of drug species to the brain is ofttimes seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier or BBB. Site-specific delivery and sustained delivery of drugs to the brain are even more difficult, and to date (i.e. prior to the dates of applicant's earlier applications) no useful simple or generic techniques to achieve such phenomena are known to the art.
Previously, it has been suggested to deliver a drug species, specifically N-methylpyridinium-2-carbaldoxime chloride (2-PAM), into the brain, the active nucleus of which in and of itself constitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Such approach was conspicuously delimited to relatively small molecule quaternary pyridinium ring-containing drug species and did not provide the overall ideal result of brain-specific, sustained release of the desired drug, with concomitant rapid elimination from the general circulation, enhanced drug efficacy and decreased toxicity. Hence, no "trapping" in the brain of the 2-PAM formed in situ resulted, and obviously no brain-specific, sustained delivery occurred as any consequence thereof: the 2-PAM was eliminated as fast from the brain as it was from the general circulation and other organs. Compare U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5, pp. 685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. A more recent extension of this approach is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09, March 1983, p. 2910B.
It has also previously been speculated to deliver, e.g., an antitumor agent, into the brain by utilizing a dihydropyridine/pyridinium redox carrier moiety therefor, but this particular hypothesis necessarily entails derivatizing the dihydropyridine/pyridinium carrier with a substituent itself critically designed to control the release rate of the active drug species from the quaternary derivative thereof, as well as being critically functionally coordinated with the particular chemical and therapeutic activity/nature of the antitumor drug species itself; Bodor et al, J. Pharm. Sci., supra. See also Bodor, "Novel Approaches for the Design of Membrane Transport Properties of Drugs", in Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Roche, E. G. (ed.), APhA Academy of Pharmaceutical Sciences, Washington, D.C., pp. 98-135 (1976). Moreover, the hypothesis does not include any indication of what chemical transformations would be needed to link any specific antitumor agent (or indeed any specific drug) to an appropriate carrier moiety.
Accordingly, acutely serious need exists in this art for a truly effective generic but nonetheless flexible method for the site-specific, or sustained delivery, or both, or drug species to the brain, while at the same time avoiding the aforesaid noted and notable disadvantages and drawbacks associated with penetration of the blood-brain barrier, with dihydropyridine latentiated prodrug forms of drug species themselves comprising a pyridinium salt active nucleus, and with the necessity for introducing critically coordinated and designed, release rate-controlling substituents onto any particular drug/carrier moiety. This need has been addressed by applicant's earlier applications referred to hereinabove, and especially by the Ser. Nos. 379,316, 516,382 and 665,940. Thus, a major object of the invention disclosed and claimed in my '316, '382 and '940 applications is the provision of just such a generic method for the site-specific/sustained delivery of centrally acting drug species to the brain, by administering to a patient in need of such treatment an effective amount of the target drug species [D] tethered to a reduced, blood-brain barrier penetrating lipoidal form [DHC] of a dihydropyridine.revreaction.pyridinium salt type redox carrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type drug/carrier entity [D-QC].sup.+ prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/drug species results in sustained delivery of the drug [D] in the brain and facile elimination of the carrier moiety [QC].sup.+.
Another object of said '316, '382 and '940 invention is to provide for brain-specific drug delivery utilizing a dihydropyridine.revreaction.pyridinium salt carrier type redox system, which drug/carrier system is characterized by enhanced drug efficacy and decreased toxicity. Indeed, consistent therewith systemic toxicity is significantly reduced by accelerating the eliminaion of the drug/quaternary carrier system, and even central toxicity is reduced by providing a low level, sustained release of the active drug species in the brain.
In capsule summary, my '316, '382 and '940 invention features a dihydropyridine.revreaction.pyridinium salt carrier redox system for the specific and sustained delivery of drug species to the brain according to the following Scheme 1: ##STR2## Consistent with the foregoing Scheme 1, any drug species [D] is coupled to a quaternary pyridinium salt carrier [QC].sup.+ and the prodrug [D-QC].sup.+ which results is then reduced chemically to the lipoidal dihydro proprodrug form [D-DHC]. Alternatively, the drug species [D] can be directly coupled to the dihydro carrier [DHC] in certain instances to yield said pro-prodrug form [D-DHC]. After administration of the [D-DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH coenzyme system) to the ideally inactive original [D-QC].sup.+ quaternary salt prodrug, which, because of its ionic, hydrophilic character, is rapidly eliminated from the general circulation of the body, while the blood-brain barrier prevents its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D-QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (k.sub.6 &gt;&gt;k.sub.2). Because of the facile elimination of [D-QC].sup.+ from the general circulation, only minor amounts of drug are released in the body (k.sub.3 &gt;&gt;k.sub.4); [D] is released primarily in the brain (k.sub.4 &gt;k.sub.2). The overall result is a brain-specific, sustained release of the target drug species. Cf. Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372; The Friday Evening Post, Aug. 14, 1981, Health Center Communications, University of Florida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. See also Bodor er al, J. Med. Chem., Vol. 26, March 1983, pp. 313-317; Bodor et al, J. Med. Chem., Vol. 26, April 1983, pp. 528-534; Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (April 1983); Bodor et al, Science, Vol. 221, July 1983, pp. 65-67; and Bodor et al, J. Pharm. Sci., Vol. 73, No. 3, March 1984, pp. 385-388.
It is known to this art that Parkinsonism, a striatal dopamine deficiency syndrome [H. Ehringer and O. Hornykiewicz, Klin. Wsch., 38, 1236 (1960)], cannot be treated directly with dopamine, for dopamine and related catecholamines also do not cross the bloodbrain barrier [B. E. Roos and G. Steg, Life Sci., 3, 351 (1964)]. L-Dopa, considered as a prodrug for dopamine, was first discovered to be useful in the treatment of Parkinsonism more than twenty years ago [A. Barbeau, Excepta Medica, Int. Congr. Ser., 38, 152 (1961); W. Birkmayer and O. Hornykiewicz, Wien. Klin. Wochnenschr., 73, 787 (1961)]. Indeed, L-Dopa is considered to be the best available treatment for Parkinsonism, but, unfortunately, at the expense of a wide variety of undesirable side effects [A. Barbeau, TIPS, 2 (11), 297 (1981)]. The peripheral side effects of L-Dopa, which range from nausea and vomiting to cardiac arrythmias and hypotension, appear to be due to one or more of the metabolic products thereof, rather than L-Dopa per se. L-Aromatic amino acid decarboxylase enzyme is responsible for the major metabolism of L-Dopa, whether prior, during or after absorption. Concurrent administration of L-Dopa with an inhibitor of aromatic amino acid decarboxylase, which should not be able to penetrate the BBB, reduces the decarboxylation of L-Dopa in peripheral tissues. Such reduction allows higher proportions of L-Dopa to reach the CNS and at the same time diminishes the peripheral side effects considerably, particularly vomiting and cardiac arrythmias, but a number of serious side effects still persist [A. Barbeau, TIPS, supra; A. Barbeau and M. Roy, Neurology, 26, 399 (1976)]. Attempts have also been made to alleviate the well-known dissolution, absorption and metabolism problems of L-Dopa [H. Ninterberger, Biochem. Med., 5, 412 (1971); H. Shindo, T. Komai, K. Tanaka, E. Nakajima and N. Miyakoshi, Chem. Pharm. Bull., 21, 826 (1973); C. O. Rutledge and M. M. Hoehn, Nature (London), 244, 447 (1973); R. L. Bronaugh, R. J. McMurty, M. M. Hoehn and C. O. Rutledge, Biochem. Pharmacol., 24, 1317 (1975)], employing prodrug approaches [N. Bodor, K. B. Sloan, T. Higuchi and K. Sasahara, J. Med. Chem., 20, 1435 (1977); A. M. Felix, D. P. Winter, S. S. Wang, I. D. Kulesha, W. R. Pool, D. L. Hane and H. Sheppard, J. Med. Chem., 17, 422 (1974)].
Additionally, dopamine agonists, which are used in the treatment of hyperprolactinemia associated with pituitary adenomas or amenorrhea [R. F. Spark and G. Dickenstein, Ann. Int. Med., 90, 949 (1979)], also induce unwanted side effects. The use of dopamine agonists in the treatment of hyperprolactinemia is based on the ability of these compounds to supress the production of prolactin. While the incidence of hyperprolactinemia in the general population is difficult to determine, it has been estimated that hyperprolactinemia is the most frequent endocrine disease and represents 10% of all such disorders [Riskin et al, "Management of Pituitary Secretory Adenomas", in Harrison's Updates on Internal Medicine, Vol. 3, eds. K. J. Isselbacher, R. D. Adams, E. Braunwald, J. B. Martin, R. G. Peterodorf and J. W. Wilson, McGraw-Hill Publishing Co., New York, 235-252 (1982)]. Hyperprolactinemia can be caused by micro- or macro-adenomas of the anterior pituitary gland (Post et al., The Pituitary Adenoma, Plenum Publishing Co., New York, 1980); by defects in the tuberoinfundibular dopamine system, which tonically inhibits prolactin secretion [MacLeod et al, "Regulation of the Synthesis and Release of Prolactin", in Lactogenic Hormones, eds., G. E. W. Wolstenholme and J. Knight, Churchill Livingstone Press, Edenburgh, England, 53 (1972)]; by chronic excessive estrogen exposure [Ben-Jonathan et al, Endocrinology, 106, 690 (1980)]; or by defects within the anterior pituitary gland itself. Additionally, hyperprolactinemia can occur during and after chronic use of oral contraceptives and therapy with neuroleptics [Riskin et al, supra; Fluckiger, "Pharmacology of Prolactin Secretion", in Treatment of Pituitary Adenomas, eds. R. Fahlbusch and K. V. Werder, PSG Publishing Co., Stuttgart, Germany, 351-360 (1978)]. Interestingly, the most common hyperprolactinemia occurs physiologically during late gestation and in response to the suckling stimulus (MacLeod et al, supra).
Costello [Am. J. Phathol. 12, 205-216 (1936)] observed nearly 50 years ago that 22.5% of anterior pituitaries obtained from unselected autopsies had adenomas. This astonishing finding was given little credence until very recently when several studies observed an incidence of pituitary tumors of 4.8 to 27%, with most frequent incidence being 22.5 to 27% [Costello, supra; Gold, Epidemiol. Rev., 3, 163-183 (1981); Bloodworth et al, "Electron Microscopy of Pituitary Tumors", in Recent Advances in the Diagnosis and Treatment of Pituitary Tumors, ed. J. A. Linfood, Raven Press, New York, 1-159 (1979); McComb et al, Arch. Phathol. Lab. Med., 107, 488-491 (1983)]. Thus, it is reasonable to assume that approximately 25% of the general population has pituitary adenomas. The incidence of anterior pituitary tumors is much more frequent in women than men. Peak incidence occurs between the ages of 30 and 60 [Karduck et al., "Transmaxillar-Transsphenoidal Hypophysectomy: Approach and Rhinological Follow-up", in Treatment of Pituitary Adenomas", eds. R. Fahlbusch and K. V. Werder, PSG Publishing Co., Stuttgart, Germany, 299-304 (1978)].
With the advent of immunohistochemical methods to define the hormonal type of anterior pituitary tumors, it has been determined that 40 to 70% of these adenomas secrete prolactin [Post et al, supra; McComb et al, supra; Hardy, in Pituitary Microadenomas, eds. G. Faglia, M. A. Giovanelli and R. M. MacLeod, Academic Press, London, p. 7 (1980); Lancranjan, "Increasing Use of Dopamine Agonists as the First Choice Therapy of Prolactin-secreting Adenomas", in A Clinical Problem: Microadenoma Diagnosis and Treatment, ed. G. M. Molinatti, Excerpta Medica Press, Amsterdam, 103-113 (1982); and many others]. The presence of this high incidence suggests that prolactin secreting cells are more susceptible than other pituitary cell types to neoplastic transformation. Additionally, hyperprolactinemia is associated in 30 to 40% of cases with growth hormone-secreting tumors [Cocchi et al, "Pathophysiological Aspects of Prolactinomas", in A Clinical Problem: Microadenoma Diagnosis and Treatment, ed. G. M. Molinatti, Excerpta Medica Press, Amsterdam, 1-15 (1982)]. If one assumes that 25% of the general population has pituitary microadenomas and of these 50% are prolactinomas, then about 12.5% of the general population has prolactin-secreting microadenomas. Thus, in the United States alone, approximately 27.5 million people are in potential need of therapy for prolactinomas.
That 27.5 million people are not treated for anterior pituitary tumors is due to the fact that pituitary adenomas are diagnosed primarily from consequential reproduction problems. In women, microademonas and resulting hyperprolactinemia are frequently associated with secondary amenorrhea or galactorrhea. Up to 25% of women with secondary amenorrhea have causative hyperprolactinemia, while 30 to 90% of those with galactorrhea have chronically elevated serum prolactin [Schlechte et al, Endocrine Rev. 1, 295-308 (1980)]. In men, hyperprolactinemia is less common and is found in less than 8% of men with sexual impotence and in less than 4% of men with infertility [Millins, in Advances in Prolactin, eds. M. L'Hermite and S. L. Judd, Progress in Reproductive Biology, Volume 6, Basal Karger, p. 194). When pituitary adenomas increase in size, neurological signs such as headaches and visual field impairments occur.
While the primary treatment of macroadenomas is transsphenoidal surgery and radiotherapy, the recommended treatment for the more common microadenoma is controversial. Total removal of microadenomas is possible in up to 90% of cases with transsphenoidal surgery and menses returns in up to 75% of women and fertility is restored in 60 to 70% [Hordy, Clin. Neurosurg. 16, 185-217 (1969); Post et al, J. Amer. Med. Assoc. 242, 158-162 (1979); Tindall et al, J. Neurosurg. 48, 849-860 (1978)]. In women in whom menses and/or fertility does not return after surgery, bromocriptine therapy is usually effective [Zervas et al, New Eng. J. Med. 302, 210-214 (1980)]. In this regard, evidence for a normalization of serum prolactin levels with bromocriptine in 85% of women with microadenomas [Lancranjan, supra; Besser et al, Postgrad. Med. 52 (Suppl. 1), 64 (1976); Friesen, in Ergot Compounds and Brain Function, eds. M. Goldstein, D. B. Calve, A. Lieberman and M. O. Thorner, Raven Press, New York, p. 147 (1980); Thorner et al, in Ergot Compounds and Brain Function, eds. M. Goldstein, D. B. Calve, A. Lieberman and M. O. Thorner, Raven Press, New York, p. 165 (1980)] and recent evidence that bromocriptine and other dopamine agonists reduced the size of tumors in 126 of 258 cases [Lancranjan, supra; Corenblum, Lancet 2, 786 (1978)], suggests the usefulness of dopaminergic agents in the non-surgical management of microadenomas.
An additional use of bromocriptine is post-partum prolactin reduction in women who choose not to nurse their newborns. Also, 1% of women who use oral contraceptives fail to resume normal cycles upon cessation of contraceptive use; these women are almost invariably hyperprolactinemic and can be effectively treated with bromocriptine or other dopaminergic drugs.
Thus, especially acutely serious need exists in this art to deliver a dopaminergic agent directly and specifically to the brain, in a sustained manner, and there elicit the desired dopaminergic response, e.g., for the treatment of Parkinsonism or hyperprolactinemia. This need has been addressed by applicant's earlier applications referred to above, and especially by the Ser. No. 461,543, and is also addressed by the present application.